Major depression is a serious health problem affecting more than 5% of the population, with a lifetime prevalence of 15-20%.
Selective serotonin reuptake inhibitors have produced success in depression and related illnesses and have become among the most prescribed drugs. However, they have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in less than ⅔ of patients.
Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptor.
However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long term treatment is required before clinical improvement is achieved.
It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5HT1A receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants such as SSRIs.
A 5HT1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism (Perez, V., et. al., The Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
Thus, there remains a need for compounds which inhibit serotonin reuptake and which are antagonists of the 5HT1A receptor, useful for the treatment of, for example, depression, preferably wherein the compounds produce a rapid onset of action.